Immunization is a straightforward concept but remains for some pathogens like HIV-1 a challenge. Thus, new
approaches towards increasing the efficacy of vaccines are required to turn the tide. There is increasing evidence
that antigen exposure over several days to weeks induces a much stronger and more sustained immune response
compared to traditional bolus injection, which usually leads to antigen elimination from the body within a couple
of days. Therefore, we developed a poly(ethylene) glycol (PEG) hydrogel platform to investigate the principal
feasibility of a sustained release of antigens to mimic natural infection kinetics. Eight-and four-armed PEG
macromonomers of different MWs (10, 20, and 40 kDa) were end-group functionalized to allow for hydrogel
formation via covalent cross-linking. An HIV-1 envelope (Env) antigen in its trimeric (Envtri) or monomeric
(Envmono) form was applied. The soluble Env antigen was compared to a formulation of Env attached to silica
nanoparticles (Env-SiNPs). The latter are known to have a higher immunogenicity compared to their soluble
counterparts. Hydrogels were tunable regarding the rheological behavior allowing for different degradation
times and release timeframes of Env-SiNPs over two to up to 50 days. Affinity measurements of the VCR01
antibody which specifically recognizes the CD4 binding site of Env, revealed that neither the integrity nor the
functionality of Envmono-SiNPs (Kd = 2.1 ± 0.9 nM) and Envtri-SiNPs (Kd = 1.5 ± 1.3 nM), respectively, were
impaired after release from the hydrogel (Kd before release: 2.1 ± 0.1 and 7.8 ± 5.3 nM, respectively). Finally,
soluble Env and Env-SiNPs which are two physico-chemically distinct compounds, were co-delivered and shown
to be sequentially released from one hydrogel which could be beneficial in terms of heterologous immunization
or single dose vaccination. In summary, this study presents a tunable, versatile applicable, and effective delivery
platform that could improve vaccination effectiveness also for other infectious diseases than HIV-1.